SBIR-STTR Award

Chemical probes will be developed to profile toxicities resulting from drug interactions. We have developed fluorescent probes that exclusively identify active members of the serine hydrolase super-family of enzymes. Using our technique, we can elucidate activity profiles of diseases, and broadly investigate interactions between the proteome and potential therapeutics. This technology could be used to determine molecular toxicological profiles, rapidly and inexpensively, early in the drug development process. To expand the range of detectable toxicologies, we will design, synthesize, and characterize probes for the following pharmacologically interesting families: kinases, phosphatases, and cytochromes P450. Phase I will demonstrate the use of our current probes in investigating the protein interactions of various inhibitors of enzymes implicated in the etiology of diabetes, obesity, and Alzheimers disease. In phase II we will design and synthesize probes for kinases, phosphatases, cytochromes P450, and cysteine proteases. Phase II will include profiling various compounds and tissue sources, identifying toxicological markers, and creating a database of tissue-specific protein-compound interactions. PROPOSED COMMERCIAL APPLICATIONS: A service for accurately screening potential drugs for toxicity before animal trials will be commercialized. The database component will also be marketed for interrogation with proteomas, targets, or compounds.

Thesaurus Terms:
chemical synthesis, drug adverse effect, drug interaction, fluorescent dye /probe, protein engineering, protein structure function, proteomics, serine proteinase, toxicology peptidyl dipeptidase, protein protein interaction biotechnology

ActivX Biosciences (ActivX) will develop and validate a novel toxicoproteomics platform to correlate changes in protein activity with compound toxicology. This platform uses fluorescent chemical probes to interrogate catalytically active proteins related by super-family derived from any biological sample. Alterations in protein activity are expected to be more interpretable and relevant to toxicant molecular mechanism than the more commonly used transcript-profiling approaches. This Phase II study will demonstrate the utility of this protein activity platform. This study has several stages. 1) The platform will be established as a predictive platform for compound toxicity by investigating protein activities of a) cell lines and b) tissues from animals exposed to compounds that have been well-studied using pharmacology, genomics, and other techniques. 2) The resulting protein activity profiles will be integrated into a database that also includes publicly available transcription data, and will allow for seamless correlation of treatments with changes in protein activity levels of the serine hydrolase, cysteine protease, kinase, epoxide hydrolase, and glutathione-S-transferase families. The activity-based probes (ABPs) for some of these enzyme families are cell-permeable, which is a useful feature that allows for in vivo, rather than in vitro measurements of protein activity in cell lines. 3) Cell-permeable derivatives of ABPs that are currently not cell permeable will be synthesized. 4) To expand the breadth of our profiling abilities, ActivX will also design, synthesize and validate ABPs for the phosphatase and cytochrome P450 families. This platform will be useful for detecting toxicity of chemicals, including therapeutics, and will be important for classifying and exploring the molecular basis of toxicities. Therefore, this technology has a great potential for reducing the time and cost in early compound development, and for revealing underlying toxicity mechanisms of different compounds. ActivX plans to commercialize its technology by establishing a toxicoproteomic database, and by providing a service to the pharmaceutical industry that will detect toxicities of compounds early in the drug screening process.

Thesaurus Terms:
chemical synthesis, drug adverse effect, drug interaction, fluorescent dye /probe, nucleic acid probe, protein engineering, protein structure function, proteomics, serine proteinase, toxicology endopeptidase, peptidyl dipeptidase, protein protein interaction biotechnology, laboratory mouse, peptide chemical synthesis